Axial shielding of Pd(II) complexes enables perfect stereoretention in Suzuki-Miyaura cross-coupling of Csp3 boronic acids

Abstract

Stereocontrolled Csp³ cross-coupling can fundamentally change the types of chemical structures that can be mined for molecular functions. Although considerable progress in achieving the targeted chemical reactivity has been made, controlling stereochemistry in Csp³ cross-coupling remains challenging. Here we report that ligand-based axial shielding of Pd(II) complexes enables Suzuki-Miyaura cross-coupling of unactivated Csp³ boronic acids with perfect stereoretention. This approach leverages key differences in spatial orientation between competing pathways for stereoretentive and stereoinvertive transmetalation of Csp³ boronic acids to Pd(II). We show that axial shielding enables perfectly stereoretentive cross-coupling with a range of unactivated secondary Csp³ boronic acids, as well as the stereocontrolled synthesis of xylarinic acid B and all of its Csp³ stereoisomers. We expect these ligand design principles will broadly enable the continued search for practical and effective methods for stereospecific Csp³ cross-coupling.

Fig. 1

Challenges in stereocontrolled Csp³ couplings. a Stereoselective couplings vs. stereospecific couplings. b Competing stereodivergent stereospecific transmetalation pathways. c Axial shielding—a ligand design principle for controlling stereochemistry in Csp³ couplings. Projecting steric bulk above and below the Pd (II) square plane should selectively inhibit stereoinvertive transmetalation, thus favoring stereoretention

Fig. 2

Tuning of ligand sterics. a Crystal structure of {[(2-Me-Ph)₃P]Pd(4-nBu-Ph)(Br)}₂ and concept of blocking of the axial sites on Pd. b Model coupling reaction for optimizing ligands (ortho-substituent optimization) Pd(PPh₃)₄ was used due to insufficient yield with Pd₂dba₃/PPh₃. c Crystal structure of {[(2-Bn-Ph)₃P]Pd(4-OMe-Ph)(Br)}₂ is consistent with the axial shielding ligand design principle. d % es and b/l ratio do not necessarily correlate as a function of ligand structure

Fig. 3

Tuning of ligand electronics. The effect of ligand electronic tuning on stereooutcome and b/l ratio under both anhydrous (a) and biphasic (b) conditions (%branched = %b–%l). c Electronic tuning of L4 leads to perfect enantiospecificity for the cross-coupling of challenging substrate (S)-1a

Fig. 4

Substrate scope of the sterospecific cross-coupling reaction. a Reaction conditions. b Scope of the Csp³ boronic acid coupling partner, (^§: no improvement when using L2, ^*: branched on C3/branched on C2/linear (Supplementary Figure 5), ^#: L2 was used, L4 gave lower yields). c Scope of the bromide coupling partner. All reactions were performed in duplicate. Branched/linear ratios were determined by HPLC or GC analysis of the crude reaction using an authentic linear product standard. Yields were determined by isolation. Enantiospecificities were determined by chiral HPLC of the purified product

Fig. 5

Building block-based synthesis of all possible Csp³ stereoisomers of xylarinic acid B. a Conditions for deprotection and coupling. b Air-stable BIDA boronate building blocks prepared by resolution. c Xylarinic acid B and all possible Csp³ steroisomers accessed by stereospecific cross-coupling of stereodefined building blocks. % ds, b/l, and yield refer to the cross-coupling step